Triazole-benzodiazepine derivatives, such as alprazolam, triazolam, brotizolam, etizolam, etc., are marketed for therapeutic indications such as anxiety disorder and adjunctive treatment for depression.
The general scheme for preparation of the triazole-benzodiazepine derivatives is as follows:
where R is
(the spiral line indicates the side that is attached to the benzodiazepine nucleus), and X is hydrogen or halogen, i.e. chlorine, fluorine, bromine or iodine.
From the above mentioned general scheme, it appears that there is a common strategy for synthetic preparation of the triazole-benzodiazepine derivatives involves triazol ring formation as a common step. The benzodiazepine moiety (Formula A) required for synthesis can be prepared from corresponding suitable benzophenone derivatives which is commonly described in the literature. The synthesis of triazol-benzodiazepine involves a common step of cyclization and formation of the triazol ring from acetyl hydrazone derivatives (Formula B) derived from different benzodiazepine. The formation of acetyl hydrazone derivatives and its cyclization forms a common synthetic scheme in various triazol-benzodiazepines, such as alprazolam, triazolam, brotizolam and etizolam etc.
Therefore, the present invention aims to develop a convenient process of cyclization of acetyl hydrazone derivatives (Formula B) to obtain Formula C.
U.S. Pat. No. 3,987,052 to Hester et al. describes various strategies for the formation of benzodiazepine-triazol moieties in patent which involves the following steps:
According to the above patent, 1,3 dihydro-5-phenyl-2H-1,4 benzodiazepine-2-thione of formula (I) in ethanol when condensed with acetyl hydrazide (II) at a temperature range of 60-120° C. for 24 hours obtained a crude mixture comprising of corresponding 2-(2-acetyl hydrazino)-5-phenyl-3H-1,4 benzodiazepine (III) and the corresponding 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-I] [1,4]benzodiazepine (IV). Further purification by conventional methods, such as extraction or chromatography, is required to obtain the compound IV with a yield of 47.7%.
From commercial point of view, above said preparation is tedious and lengthy as well as expensive due to low yield due to concomitant formation of compounds III and IV.
According to Croatian Patent No. HR-P2001000081, alprazolam was prepared by cyclization of acetyl hydrazone using tri-ethyl ortho acetate in presence of catalyst as follows:
Tri-ethyl ortho acetate is a flammable liquid which is difficult to handle on industrial scale. Additionally, the catalyst used in the above cyclization process is expensive, as well as being unavailable commercially, due to its high manufacturing cost.
In patent DE 3413709 A, the title compound I
(R1=H, C1-3 alkyl; R2 to R5=H, C1-3 alkyl, halo) were prepared by mesylating the alcohol II
(R═H) and cyclizing the product III
(R═SO2Me) with aqueous NH4OH—C1-3 alkanol. Mesylating the alcohol II (R, R2—R4=H, R1=Me, R5=Cl) in DMF, THF, and NEt3 with MeSO2Cl-THF at −10° C. over 30 min, then stirring 30 min, filtering, and treating the filtrate (containing the compound III (R═SO2Me)) with aqueous NH4OH—MeOH gave alprazolam (I, R1=Me, R2—R4=H, R5=Cl).
The drawbacks of the above mentioned processes are requiring more operations to obtain the triazol-benzodiazepine derivatives with critical parameters, and requiring the use of reagents such as methane sulphonyl chloride-tetra hydro furan (THF) at −10° C.
Therefore, there is a need in the art to provide a cost-effective and ecologically friendly process for preparation of triazol-benzodiazepine derivatives, such as alprazolam, triazolam, brotizolam and etizolam. Accordingly the present invention provides a process which is devoid of the use of expensive and hazardous reagents, and of critical reaction parameters. Also, the solvent used as reaction medium is recovered to a greater extent after the completion of reaction which makes the process commercially applicable for industrial scale.